Identification of First-in-Class Inhibitors of Kallikrein-Related Peptidase 6 That Promote Oligodendrocyte Differentiation

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) that causes severe motor, sensory, and cognitive impairments. Kallikrein-related peptidase (KLK)6 most abundant serine protease secreted in CNS, mainly by oligodendrocytes, myelin-producing cells KLK6 assumed to be a robust biomarker MS, since it highly increased cerebrospinal fluid (CSF) MS patients. Here, we report design biological evaluation KLK6’s low-molecular-weight inhibitors, para-aminobenzyl derivatives. Interestingly, selected hit compounds were selective proteolytic network encompassing KLK1 plasmin also participate development physiopathology. Moreover, hits found noncytotoxic on primary cultures murine neurons oligodendrocyte precursor (OPCs). Among them, two (32 42) shown promote differentiation OPCs into mature oligodendrocytes vitro constituting thus emerging leads for regenerative therapies.